Heart failure is a leading cause of cardiovascular mortality in the US and Europe and is a ‘hallmark’ of dilated cardiomyopathy, a multifactorial disease in which there is evidence of enteroviral infection in up to 30% of cardiomyopathy patients. Despite the relative prevalence of these infections, however, diagnosis remains extremely difficult. At present, enteroviral infections of the heart may only be confirmed by biopsy, but even the assay used on biopsy samples is neither sensitive nor specific.
In cardiac muscle, the dystrophin-glycoprotein complex includes dystrophin and the dystrophin-associated glycoprotein, β-sarcoglycan, β-dystroglycan; and the recently described sarcospan. This complex is part of the extrasarcomeric cytoskeleton that collectively connects the internal F-actin-based cytoskeleton to laminin-2 of the extracellular space. Thereby, it is thought to play an important role in the transmission of mechanical force to the extracellular matrix.
Genetic defects in these proteins are the cause of human limb-girdle muscular dystrophy type 2D, 2E, 2C, and 2F, and can caused dilated cardiomyopathy in humans. Mutations in dystrophin also cause Duchenne and Becker muscular dystrophy, both of which have a high incidence of dilated cardiomyopathy. In addition, dystrophin mutations are a cause of X-linked dilated cardiomyopathy. These studies and others have led to the paradigm that familial dilated cardiomyopathy can result from defective transmission of mechanical force from the sarcomere to the extracellular matrix and that disruption of the dystrophin-glycoprotein complex may be a common mechanism that causes cardiomyopathy.
Although the importance of genetic defects of the dystrophin-glycoprotein complex in hereditary cardiomyopathy is well established, little is known about its role in acquired cardiomyopathy. A subset of human acquired dilated cardiomyopathy is associated with an enteroviral infection of the heart, in particular, coxsackie B viruses. Coxsackie B viruses are members of the picorniaviridae family, enterovirus genus.
The inventors' work has indicated that enteroviral protease 2A cleavage of dystrophin plays a role in the molecular pathogenesis of enterovirus-induced cardiomyopathy. However, the mechanisms by which enterovirus infection can cause cardiomyopathy are not clear, and no diagnostic test directed to cleavage products of dystrophin in the heart that would allow for early treatment or prognosis is available.